We propose to develop an inexpensive, yet very high quality detector system for protein crystallography, using Active Pixel Matrix CMOS (complementary metal-oxide-semiconductor) technology. We have based this effort on an existing CMOS imaging system for X rays, manufactured by Rad-icon Imaging Corporation. During Phase I of this proposed project, we increased the active area of the existing detector module 4-fold, by doubling its pixel size from 485m to 965m. Full-scale (50mm x 100mm) prototypes were fabricated and tested. We decreased its total noise by half, and we increased its readout precision from 12-bit (1 part in 4,096) to 14- bit (1 part in 16,384). Finally, we fabricated small (16pixel x16pixel) prototype devices whose readout was redesigned with 16-bit, correlated double sampling (CDS). We test these devices and verified that CDS reduces the readout noise by up to a factor of 6. In Phase II, we will fabricate full-sized sensors with correlated double sampling. We will also incorporate additional noise suppression technology, particularly multiple non-destructive readout. By fabricating the new sensors with multiple readout ports, we enable parallel readout, so we can read each pixel many (16) times in less than one second, thus improving the reliability of each measurement. These technical improvements will reduce noise sufficiently that we can implement 16-bit precision readout such that the noise is less than one part in 65,536 of the total range of the detector. We will then develop a complete detector system, incorporating 12 of these modules in a 2x6 array, covering an area of 20cm x 30cm. This system will be cooled to -600C, to reduce the noise even more. The X-ray detection systems we plan to bring to market will be technically very advanced relative to existing commercial units, yet they will cost about half as much. Our system will greatly improve the scientific effectiveness of structural molecular biology, and the cost effectiveness of their labor. PUBLIC HEALTH RELEVANCE: 1). Protein crystallography is a mature and important enabling technology for the biological sciences and in pharmaceutical development, for determining the structures of large biological molecules: proteins and nucleic acids. The present proposal would enhance the efficacy of protein crystallography, by improving the X-ray detector these scientists use in their home laboratory, to record the diffraction data from protein crystals they have grown. The detector we wish to develop is faster, higher-resolution, higher precision, and more efficient than the detectors now used by protein crystallographers, and it will be half the price.